Program Director/Principal Investigator (Last, First, Middle): Ko, Minoru, S.H. Dyskeratosis congenita (DKC) is a rare genetic disease that occurs at the rate of 1 in 1 million births and caused by mutations in genes involved in the regulation of telomere lengths. Although there are multiple gene mutations causing DKC, all the patients carry significantly shorter telomeres and eventually develop bone marrow failure, which is the main cause of premature mortality in DKC patients. There has been no effective treatment for DKC patients. Here, we would like to propose the product of human ZSCAN4 gene as a biologic to treat DKC patients. We have originally identified mouse Zscan4, a novel protein expressed specifically in 2- cell stage mouse embryos, and have published a number of unusual features of Zscan4 functions in mouse ES cells: (i) to rapidly extend telomeres by homologous recombination (called alternative lengthening of telomeres), which is independent of telomerase (ii) to increase genome stability and maintain normal karyotype by transient and occasional expression, (iii) to increase developmental potential, (iv) to block de novo synthesis of proteins transiently, (v) to increase the efficiency and quality of induced pluripotent stem (iPS) cells, when used as one of the reprogramming factors, and (vi) to function as a potent epigenetic modifier and transiently open chromatin. Based on these functions of mouse Zscan4, we hypothesize that transient overexpression of human ZSCAN4 protein extends telomeres in bone marrow cells from DKC patients by homologous recombination-based mechanisms and eventually alleviates bone marrow failure in DKC patients. In this SBIR Phase I proposal, we would like to demonstrate that transient overexpression of ZSCAN4 elongates telomeres in fibroblast cells derived from DKC patients. We would also like to demonstrate that ZSCAN4 biologics can be delivered to bone marrow using a mouse model. The proposed project, if successful, will offer a first step towards a dramatically new therapy for patients with DKC. In addition, the biologic's mechanisms are very much applicable to other related bone marrow and telomere related disorders, such as myelodysplastic syndrome and Fanconi anemia. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page